Recent findings in my laboratory have provided a potential link between the normal response to inflammatory stimuli and mechanisms which may inititate the atherosclerotic process. The modifications which we have observed in extravascular low density lipoproteins (LDL) of interstitial inflammatory fluid bear striking similarity to LDL particles recovered from human atherosclerotic arteries and modified LDL particles produced by interaction with arterial cells in vitro. Lipoproteins modified in vitro have been demonstrated to be taken up and degraded by monocyte/macrophages at a significantly faster rate than unmodified lipoproteins. The presence of modified lipoproteins in the extravascular space may be representative of lipoprotein modification occurring in interstitial fluid of the arterial wall, and may indicate how scavenger cells develop into lipid-laden foam cells. Utilizing the sponge implant model, lipoproteins will be prepared from interstitial inflammatory fluid and homologous plasma derived from rabbits fed both normal laboratory chow and with moderate diet-induced hypercholesterolemia. Inflammatory fluid will also be obtained from Watenabe Heritable Hyperlipidemic rabbits as available. Lipoproteins from all of these sources will be characterized according to density, particle size, electrophoretic mobility, morphology and chemical composition. Selected fractions will be utilized for comparative studies of binding, internalization and degradation by macrophages and arterial cells in vitro. Additional studies will be performed with chemically modified lipoproteins (acetylation, malondialdehyde treatment, etc.) to compare their uptake and metabolism by macrophages with inflammatory fluid lipoproteins. And finally we shall conduct turnover studies of isotopically labeled lipoproteins derived from plasma and inflammatory fluid introduced into both the vascular and extravascular compartments of recipient animals. With these experiments we hope to establish the mechanisms of lipoprotein modification in the inflammatory response and to further our knowledge as to how cells of the monocyte-macrophage system may be stimulated in vivo to transform into foam cells. In this regard study of lipoprotein metabolism in interstitial inflammatory fluid may prove to be an important model in our understanding of the etiology of atherosclerosis.